Chemotherapy is a primary therapy in many brain malignancies, but efficacy is limited by the low permeability of the blood-brain barrier (BBB) and blood-tumor barrier. The overall hypothesis guiding the OHSU Blood-Brain Barrier Program for the past three decades has been that increasing chemotherapy delivery across the BBB and dose intensity within the cancer cells will improve anti-tumor efficacy. However, in addition to tumor cell toxicity, chemotherapy agents also induce oxidative stress in normal tissues causing toxic side effects such as ototoxicity and nephrotoxicity that can lead to dose reductions and decreased quality of life. The platinum-based chemotherapeutic cisplatin, commonly used for brain tumor therapy in pediatric patients, causes progressive hearing loss in over 80% of patients with medulloblastoma. We have investigated the use of thiols that mimic the activity of the endogenous antioxidant glutathione to protect against oxidative stress and to reduce chemotherapy toxicities. Our preclinical and clinical NIH-funded studies of chemoprotection with sodium thiosulfate (STS) have led to two Phase III cooperative group trials. The Children's Oncology Group (COG) trial ACCL0431 clearly showed that delayed STS protected against hearing loss in children receiving cisplatin, but also showed the need for further improvement in hearing protection. In Specific Aim 1 we will investigate strategies to improve chemoprotection using both STS and N-acetylcysteine (NAC) against the toxicities of cisplatin and other alkylating chemotherapy. The COG trial and a trial conducted by the International Society of Pediatric Oncology both showed no impact of delayed STS on cisplatin efficacy in localized standard risk cancers; however, a small post hoc analysis of the COG trial did show tumor protection in patients with disseminated disease. We hypothesize that disseminated medulloblastoma will require further dose intensification and therefore additional chemoprotection strategies. Specific Aim 2 will assess the impact of chemoprotection on chemotherapy efficacy in rat models of disseminated medulloblastoma and investigate mechanisms by which disseminated disease differs from localized tumors. We will investigate new approaches to improve chemotherapy efficacy by dose escalation, enhancing delivery with BBB disruption or increasing chemotherapy toxicity by depleting glutathione concentrations. Specific Aim 3 will further translate our chemoprotection strategies to the clinic. We will conduct a phase I dose escalation study to determine the NAC dose that can safely be given in combination with STS to achieve plasma levels needed for chemoprotection, in children with localized disease who undergo treatment with cisplatin-based chemotherapy. In addition, we will determine the association between hearing and quality of life in a unique large cohort (n = 160) of childhood cancer survivors who were treated at a young age with cisplatin at OHSU. We hypothesize that by modulating the timing and route of administration of chemo-enhancers, chemotherapy, and chemoprotection, toxicity can be decreased while maintaining or increasing anti-tumor efficacy.